Process for preparing pyridyl-substituted pyrazoles

ABSTRACT

The present invention relates to a process for preparing 1-pyridyl-substituted pyrazoles, comprising the reaction of acetyleneketones with pyridylhydrazine derivatives to give 1-pyridyl-substituted dihydro-1H-pyrazoles, the further reaction thereof with elimination of water to give 1-pyridyl-substituted trihalomethylpyrazoles, and the further processing thereof.

The present invention relates to a process for preparing1-pyridyl-substituted pyrazoles, comprising the reaction ofacetyleneketones with hydrazine derivatives to give1-pyridyl-substituted dihydro-1H-pyrazoles, the further reaction thereofwith elimination of water to give 1-pyridyl-substitutedtrihalomethylpyrazoles, and the further processing thereof.

1-Pyridyl-substituted pyrazoles and dihydro-1H-pyrazoles are valuableintermediates for preparation of anthianilamides, which can find use asinsecticides.

The literature has already described the formation of pyrazoles byreaction of 1,3-dicarbonyls or corresponding 1,3-bis-electrophilicreagents with monoalkyl- or arylhydrazines (Synthesis 2004, N1, pp43-52). However, it is reported that, in the case of monoalkyl- ormonoarylhydrazines, the result is a mixture of regioisomeric pyrazoles(Tetrahedron 59 (2003), 2197-2205; Martins et al., T. L. 45 (2004)4935). Attempts to obtain exclusively one regioisomer failed (JOC 2007,72822 8243-8250). Likewise described in the literature is a process forpreparing trifluoromethylpyrazoles (WO 2003/016282). Likewise describedare preparation processes for (het)aryl-substituted pyrazoles (WO2007/144100), wherein the corresponding pyrazoles are obtained byreducing diesters with DIBAL or LiAlH₄. However, very low temperaturesare required, and the use of DIBAL is uneconomic.

It is therefore an object of the present invention to provide novel,economically viable processes for preparing 1-pyridyl-substitutedpyrazole derivatives and 1-pyridyl-substituted dihydro-1H-pyrazoles,which do not have the disadvantages described above.

The object was achieved in accordance with the invention by a processfor preparing pyridyl-substituted pyrazole derivatives of the generalformula (I)

in which

-   R¹ is alkoxy, hydroxyl, aryloxy, alkylaryloxy, alkyl, cycloalkyl,    halogen,-   R² is hydroxyl, alkoxy, arylalkoxy, alkylthio, chlorine, bromine,    fluorine, iodine, O—(C═O)alkyl, O—(C═O)O-alkyl, OSO₂alkyl, OSO₂Ph,    OSO₂-haloalkyl, OSO₂-aryl,    characterized in that    acetyleneketones of the formula (II)    in which    R⁴ is a protecting group selected from (C₁-C₆)-alkyl, aryl, benzyl,    tetrahydropyran, (C═O)-alkyl, (C═O)—O-alkyl, Si(alkyl)₃.    and X is halogen    are reacted with hydrazinopyridines of the formula (III)    in which    R³ is halogen, CN, NO₂, alkyl, cycloalkyl, haloalkyl,    halocycloalkyl, alkoxy, haloalkoxy, alkylamino, dialkylamino,    cycloalkylamino,    to give 1-pyridyl-substituted dihydro-1H-pyrazoles of the formula    (IV)    in which X, R³, R⁴ are each as defined above,    the latter are optionally converted further, without preceding    isolation, with elimination of water, to 1-pyridyl-substituted    trihalomethylpyrazoles of the formula (V)    in which X, R³, R⁴ are each as defined above,    these compounds of the general formula (V)    are converted with addition of H₂SO₄, for example, to    pyrazolecarboxylic acids of the formula (VI)    in which R³, R⁴ are each as defined above,    the latter are converted, after detaching the protecting group R⁴,    to hydroxymethylpyrazole acids of the formula (VII)    in which R³ is as defined above,    and the latter are converted to compounds of the formula (I)

Surprisingly, a regioselective reaction of acetyleneketones of theformula (II) with hydrazinopyridines of the formula (III) is observed,such that the disadvantages reported in the prior art are not observed.For example, the reaction of 5-(alkoxy orbenzyloxy)-1,1,1-trichloropent-3-yn-2-ones with hydrazinepyridineaffords, in high yield, only the desired3-[benzyloxymethyl]-1-(3-chloropyridin-2-yl)-5-(trichloromethyl)-4,5-dihydro-1H-pyrazol-5-olor3-[methyloxymethyl]-1-(3-chloropyridin-2-yl)-5-(trichloromethyl)-4,5-dihydro-1H-pyrazol-5-ol.

The process according to the invention can be illustrated by thefollowing scheme (I):

The conversion of a compound of the formula (VII) to a compound of theformula (I) is illustrated by way of example using the following scheme(II).

General Definitions

In connection with the present invention, the term “halogens” (X),unless defined otherwise, comprises those elements which are selectedfrom the group consisting of fluorine, chlorine, bromine and iodine,preference being given to using fluorine, chlorine and bromine, andparticular preference to using fluorine and chlorine. Substituted groupsmay be mono- or polysubstituted, and the substituents may be the same ordifferent in the case of polysubstitutions.

Alkyl groups substituted by one or more halogen atoms (—X) (=haloalkylgroups) are, for example, selected from trifluoromethyl (CF₃),difluoromethyl (CHF₂), CCl₃, CFCl₂, CF₃CH₂, ClCH₂, CF₃CCl₂.

In connection with the present invention, alkyl groups, unless defineddifferently, are linear or branched hydrocarbon groups.

The definitions of alkyl and C₁-C₁₂-alkyl encompass, for example, themeanings of methyl, ethyl, n-, isopropyl, n-, iso-, sec- and t-butyl,n-pentyl, n-hexyl, 1,3-dimethylbutyl, 3,3-dimethylbutyl, n-heptyl,n-nonyl, n-decyl, n-undecyl, n-dodecyl.

In connection with the present invention, unless defined differently,cycloalkyl groups are cyclic saturated hydrocarbon groups.

In connection with the present invention, unless defined differently,arylalkyl groups and arylalkoxy groups are alkyl or alkoxy groups whichare substituted by aryl groups and may have an alkylene chain.Specifically, the definition of arylalkyl encompasses, for example, themeanings of benzyl and phenylethyl, and the definition of arylalkoxy,for example, the meaning of benzyloxy.

In connection with the present invention, unless defined differently,alkylaryl groups (alkaryl groups) and alkylaryloxy groups are arylgroups or aryloxy groups which are substituted by alkyl groups and mayhave a C₁₋₈-alkylene chain and may have, in the aryl skeleton or aryloxyskeleton, one or more heteroatoms which are selected from O, N, P and S.

The inventive compounds may, if appropriate, be present as mixtures ofdifferent possible isomeric forms, especially of stereoisomers, forexample E and Z, threo and erythro, and also optical isomers, but ifappropriate also of tautomers. Both the E and the Z isomers, and alsothe threo and erythro isomers, and the optical isomers, any desiredmixtures of these isomers and the possible tautomeric forms aredisclosed and claimed.

Propargyl Ether of the Formula (II)

The propargyl ethers used as starting materials in the performance ofthe process according to the invention are defined in general terms bythe formula (II)

where X is halogen, preferably fluorine, chlorine or Br, most preferablychlorine,R⁴ is a protecting group selected from (C₁-C₆)-alkyl, aryl, benzyl,tetrahydropyran, (C═O)-alkyl, (C═O)—Oalkyl, Si(alkyl)₃, preferablybenzyl, Si(Me)₃, phenyl, (C₁-C₄)alkyl, (C═O)O-tert-butyl, morepreferably (C₁-C₄)-alkyl and benzyl and (C═O)O-tert-butyl.

Examples of acetyleneketones of the formula (II) which are suitable inaccordance with the invention are

5-(benzyloxy)-1,1,1-trichloropent-3-yn-2-one,5-(benzyloxy)-1-bromo-1,1-dichloropent-3-yn-2-one,5-(benzyloxy)-1,1-dichloro-1-fluoropent-3-yn-2-one,5-(phenyloxy)-1,1,1-trichloropent-3-yn-2-one,5-(benzyloxy)-1,1,1-trifluoropent-3-yn-2-one,5-(benzyloxy)-1,1,1-trichloropent-3-yn-2-one,1,1,1-trichloro-5-(tetrahydro-2H-pyran-2-yloxy)pent-3-yn-2-one,5-(trimethylsilyloxy)-1,1,1-trichloropent-3-yn-2-one,5-(methyloxy)-1,1,1-trichloropent-3-yn-2-one.

Processes for preparing acetyleneketones are described in the prior art,for example in THL 45 (2004), 4935-4938; JOC 2002, 67, 9200-9209,

Hydrazinopyridines of the General Formula (III)

The hydrazinopyridines used according to the present invention arecompounds of the general formula (III)

in whichR³ is halogen, CN, NO₂, alkyl, cycloalkyl, haloalkyl, halocycloalkyl,alkoxy, haloalkoxy, alkylamino, dialkylamino, cycloalkylamino,R³ is preferably halogen, CN, NO₂, (C₁-C₆)-alkyl, halo(C₁-C₆)-alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,R³ is more preferably F, chlorine, bromine, iodine, CN, (C₁-C₄)-alkyl,halo(C₁-C₄)-alkyl, halo(C₁-C₄)alkoxy,R³ is most preferably fluorine, chlorine, bromine, iodine, especiallychlorine.

One example of a hydrazinopyridine suitable in accordance with theinvention is 3-chloro-2-hydrazinopyridine.

Step (1)

In a first embodiment of the present process, 2-acylated propargylethers of the formula (II) are first reacted with hydrazinopyridines ofthe formula (III). Thereafter, the intermediates formed in step (1) areconverted to the 5-trihalomethylpyrazole derivatives of the formula (V)with elimination of water (step 2).

in which X, R³, R⁴ are each as defined above.

It is considered to be surprising that the cyclization of propargylether of the formula (II) with hydrazinopyridines of the formula (III)proceeds with high regioselectivity, such that only the desiredregioisomer of the formula (IV) is formed. The compounds of the formulae(IV) and (V) are novel.

Process step (1) of the invention is performed preferably within atemperature range from −20° C. to +100° C., more preferably attemperatures of −10° C. to +70° C.

Process step (1) of the invention is generally performed under standardpressure. Alternatively, it is, however, also possible to work underreduced pressure in order to remove the water.

The reaction time is not critical and may be selected, according to thebatch size and temperature, within a range between a few minutes andseveral hours.

In the performance of the process step of the invention, 1 mol of thepropargyl ether of the formula (II) is reacted with 0.8 mol to 1.5 mol,preferably 0.9 mol to 1.2 mol, more preferably with the equimolaramount, of the hydrazinopyridine of the formula (III).

Suitable solvents are, for example, aliphatic, alicyclic or aromatichydrocarbons, for example petroleum ether, n-hexane, n-heptane,cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin, andhalogenated hydrocarbons, for example chlorobenzene, dichlorobenzene,dichloromethane, chloroform, tetrachloromethane, dichloroethane ortrichloroethane, ethers such as diethyl ether, diisopropyl ether, methyltert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran,1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; nitriles such asacetonitrile, propionitrile, n- or isobutyronitrile or benzonitrile;amides such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoramide;sulphoxides such as dimethyl sulphoxide, or sulphones such assulpholane, alcohols such as methanol, ethanol, i-propanol. Particularpreference is given to using toluene, xylene, chlorobenzene, n-hexane,cyclohexane or methylcyclohexane, ethanol, very particular preference tousing toluene, xylene, THF, methyl tert-butyl ether, ethanol,acetonitrile.

The3-[(alkoxy)methyl]-1-(pyridin-2-yl)-5-(trihaloalkyl)-4,5-dihydro-1H-pyrazol-5-olsformed can be used without preceding workup in the subsequent step (2),in which water is eliminated.

Alternatively, these intermediates can be isolated by suitable workupsteps and optionally further purification. It is then possible toeliminate water only at a later stage.Step 2. Water Elimination

in which X, R³, R⁴ are each as defined above.

For the water elimination, it is possible, for example, to use thefollowing reagents: H₂SO₄, CF₃COOH, (CH₃)₃COCl, POCl₃, polyphosphoricacid, SOCl₂, (CH₃CO)₂O, (CF₃CO)₂O, oxalyl chloride, phosgene,diphosgene.

Particular preference is given to (CF₃CO)₂O, oxalyl chloride, thionylchloride and phosgene.

Process step (2) of the invention is preferably performed within atemperature range from −20° C. to +100° C., more preferably attemperatures of −10° C. to +70° C.

Process step (2) of the invention is generally performed under standardpressure. Alternatively, it is, however, also possible to work underreduced pressure or under elevated pressure (e.g. reaction withphosgene).

The reaction time is not critical and may, depending on the batch sizeand temperature, be selected within a range between a few minutes andseveral hours.

In the performance of the process step of the invention, 1 mol of the3-[(alkoxy)methyl]-1-(pyridin-2-yl)-5-(trihaloalkyl)-4,5-dihydro-1H-pyrazol-5-olof the formula (IV) is reacted with 0.1 to 2 mol, preferably 0.2 mol to1.8 mol, more preferably with 0, 2-1 mol, of the dewatering agent. It isalso possible to perform the elimination of water with catalytic amountsof H2SO4 or CF3COOH.

Suitable solvents are, for example, aliphatic, alicyclic or aromatichydrocarbons, for example petroleum ether; n-hexane, n-heptane,cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin, andhalogenated hydrocarbons, for example chlorobenzene, dichlorobenzene,dichloromethane, chloroform, tetrachloromethane, dichloroethane ortrichloroethane, ethers such as diethyl ether, diisopropyl ether, methyltert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran,1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; nitriles such asacetonitrile, propionitrile, n- or isobutyronitrile or benzonitrile;ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone orcyclohexanone; amides such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone orhexamethylphosphoramide; sulphoxides such as dimethyl sulphoxide, orsulphones such as sulpholane. Particular preference is given to usingtoluene, xylene, chlorobenzene, n-hexane, cyclohexane ormethylcyclohexane, very particular preference to using toluene, xylene,THF, CH₂Cl₂, methyl tert-butyl ether.

Steps 3 and 4

In a further embodiment of the process according to the invention, thetrihaloalkylpyrazoles of the formula (V) are converted according to thescheme which follows to the pyrazoles of the formula (VI) or formula(VII). This prepares the alkoxycarboxylic acid of the formula (VI) byhydrolysis of the trihalomethyl group (step 3), then elimination of theprotecting group prepares the desired3-(hydroxymethyl)-1-(pyridin-2-yl)-1H-pyrazole-5-carboxylic acid (step4).

in which X, R³, R⁴ are each as defined above.

In a preferred embodiment of the process according to the invention, the2-[3-(alkoxymethyl)-5-(trihalomethyl)-1H-pyrazol-1-yl]pyridine of theformula (V) is converted directly to the3-(hydroxymethyl)-1-(pyridin-2-yl)-1H-pyrazole-5-carboxylic acid of theformula (VII).

in which X, R³, R⁴ are each as defined above.

The compounds of the formula (VII) are likewise novel.

The reaction is generally performed under acidic or basic conditions.

Preference is given to mineral acids, for example H₂SO₄, HCl, HSO₂Cl,HF, HBr, HI, H₃PO₄, or organic acids, for example CF₃COOH,p-toluenesulphonic acid, methanesulphonic acid,trifluoromethanesulphonic acid.

The reaction can be accelerated by the addition of catalysts, forexample FeCl₃, AlCl₃, BF₃, SbCl₃, NaH₂PO₄.

Basic hydrolysis is effected in the presence of organic bases such astrialkylamines, alkylpyridines, phosphazines and1,8-diazabicyclo[5.4.0]undecene (DBU), inorganic bases such as alkalimetal hydroxides, for example lithium, sodium or potassium hydroxide,alkali metal carbonates (Na₂CO₃, K₂CO₃) and acetates such as NaOAc,KOAc, LiOAc, alkoxides, for example NaOMe, NaOEt, NaOt-Bu, KOt-Bu.

Steps 6 and 9

In a further embodiment of the process according to the invention, thealkoxy group is first detached (step 6). Subsequently, the hydrolysis ofthe trihalomethyl group is undertaken (step 9).

where X and R³ and R⁴ are each as defined above.

The elimination of the protecting group depends on the definition of theR⁴ radical. If R⁴ is (C₁-C₆)-alkyl or benzyl, the elimination can beeffected in the presence of BBr₃, HCl, HI, Me₃SiI, PyHCl, FeCl₃, BF₃,and in the case of benzyl additionally by catalytic hydrogenation.Acetyl or alkylsulphonyl groups can be eliminated under basic conditions(NaOH, KOH, Na₂CO₃, NaHCO₃), and SiMe₃ in the presence of F anions.

Step 8. If R⁴ is (C₁-C₆)-alkyl or benzyl, the CX₃ group can be converteddirectly to the ester group. It is thus possible to convert compounds ofthe formula (V) directly to the compounds of the formula (I) (step 8).

whereX, R², R³ and R⁴ are each as defined above,R¹ is (C₁-C₆)-alkoxy,R¹ is preferably methoxy, ethoxy, propoxy,R² is (C₁-C₆)-alkoxy, aryl(C₁-C₆)-alkoxy,R² is preferably (C₁-C₆)-alkoxy.

For these purposes, for example, alcohols are used, for examplemethanol, ethanol, propanol, or the alcohol/HCl, alcohol/FeCl₃,alcohol/H₂SO₄ or alcohol/alkoxide (NaOMe, NaOEt, KOEt, NaOPr)combinations.

Reaction step 8 can be performed in substance or in a solvent.Preference is given to performing the reaction in a solvent. Suitablesolvents are, for example, selected from the group consisting of water,aliphatic and aromatic hydrocarbons, for example n-hexane, benzene ortoluene, which may be substituted by fluorine and chlorine atoms, suchas methylene chloride, dichloroethane, fluorobenzene, chlorobenzene ordichlorobenzene; ethers, for example diethyl ether, diphenyl ether,methyl tert-butyl ether, isopropyl ethyl ether, dioxane, diglyme,dimethylglycol, dimethoxyethane (DME) or THF; nitriles such as methylnitrile, butyl nitrile or phenyl nitrile; alcohols such as methanol,ethanol, i-propanol; amides such as dimethylformamide (DMF) orN-methylpyrrolidone (NMP), or mixtures of such solvents, particularlysuitable solvents being water, alcohols such as methanol, ethanol,i-propanol, acetonitrile, dichloromethane.

Step 7

In compounds of the formula (VIII), the CX₃ group can be converteddirectly to the ester group. It is thus possible to convert thecompounds of the formula (VIII) directly to the compounds of the formula(I) (step 7)

Step 5.

The compounds of the formula (VII) used in the performance of theprocess according to the invention are converted in a two-stage processto the compounds of the formula (I).

First, the compounds of the formula (VII) are converted with ahalogenating agent to the corresponding acid halides. At the same time,the exchange of the hydroxyl group for halogen also takes place.

in which R¹ is halogen and R² is chlorine, bromine, iodine, fluorine.

The compounds of the formula (I) in which R¹ is halogen and R² ischlorine, bromine, fluorine, iodine are novel.

To form the acid halides and to exchange hydroxyl for halogen, thefollowing reagents are suitable: SOCl₂, POCl₃, oxalyl chloride,phosgene, diphosgene, POBr₃, PBr₃, SF₄, HCF₂CF₂N(Me)₂, PI₃. Preferenceis given to SOCl₂, oxalyl chloride, POCl₃, phosgene.

The halogenation step of the invention (step 5a) is performed preferablywithin a temperature range from −20° C. to +100° C., more preferably attemperatures of −10° C. to +70° C.

The process step of the invention is generally performed under standardpressure. Alternatively, it is, however, also possible to work underreduced pressure or under elevated pressure (e.g. reaction withphosgene).

The reaction time is not critical and may, depending on the batch sizeand temperature, be selected within a range between a few minutes andseveral hours.

In the performance of the process step of the invention, 1 mol of theacid of the formula (VII) is reacted with 1.9 mol to 2.5 mol, preferably1.95 mol to 2.2 mol, more preferably with the equimolar amount (2 eq),of the chlorinating agent.

Suitable solvents are, for example, aliphatic, alicyclic or aromatichydrocarbons, for example petroleum ether, n-hexane, n-heptane,cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin, andhalogenated hydrocarbons, for example chlorobenzene, dichlorobenzene,dichloromethane, chloroform, tetrachloromethane, dichloroethane ortrichloroethane, nitriles such as acetonitrile, propionitrile, n- orisobutyronitrile or benzonitrile; amides such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methylformanilide, N-methylpyrolidone orhexamethylphosphoramide. Particular preference is given to usingtoluene, xylene, chlorobenzene, n-hexane, cyclohexane ormethylcyclohexane, methylene chloride, dichloroethane, very particularpreference to using toluene, xylene.

In step 5b, the acid halides react with alcohol to form esters of theformula (I).

Preference is given to the alcohols such as methanol, ethanol, propanol,i-propanol, cyclohexanol.

The process step of the invention is preferably performed within atemperature range from −20° C. to +100° C., more preferably attemperatures of −10° C. to +40° C.

The reaction time is not critical and may, depending on the batch sizeand temperature, be selected within a range between a few minutes andseveral hours.

In the performance of the process step of the invention, 1 mol of theacid halide of the formula (VII) is reacted with 1 to 3 eq, preferably 1eq of the alcohol. The reaction can be performed in alcohol as solvents.The halogenation and reaction with alcohol are generally performed as aone-pot reaction.

The inventive compounds of the formula (I) are valuable intermediates inthe synthesis of anthianilamides (WO 2007/112893, WO 2007/144100).

PREPARATION EXAMPLES Example 1

5-(Benzyloxy)-1,1,1-trichloropent-3-yn-2-one,5-(Benzyloxy)-1-bromo-1,1-dichloropent-3-yn-2-one were prepared frombenzyl propargyl ether, butyl-Li and CCl₃COOEt as described in THL 45(2004) 4935-4938.

Example 23-[(Benzyloxy)methyl]-1-(3-chloropyridin-2-yl)-5-(trichloromethyl)-4,5-dihydro-1H-pyrazol-5-ol

5-(Benzyloxy)-1,1,1-trichloropent-3-yn-2-one (2.9 g, 0.01 mol) and3-chloro-2-hydrazinopyridine (1.43 g, 0.01 mol) were initially chargedin 20 ml of methyl tert-butyl ether (exothermic), and the mixture wasstirred at 30° C. for a further 1 h. The solvent was concentrated byrotary evaporation and the resulting mixture was analysed by means ofLC/MS. Only one isomer at m/e 435 was identified. The yield was 94%, thepurity 92% (area percent).

Characterization:

¹H NMR (CDCl₃): 3.5 [(1H, d (19 Hz)]; 3.84 [(1H, d, 19 Hz)]; 4.32 (2H,s); 4.52 (m, 2H), 7.1 (1H, m); 7.3-7.4 (5H, m); 7.8 [(1H, d, 2 Hz)]; 8.1[(1H, d, 2 Hz)] ppm.

Melting point (m.p.): 112-113° C.

Example 31-(3-Chloropyridin-2-yl)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-5-(trichloromethyl)-4,5-dihydro-1H-pyrazol-5-ol,mixture of two diastereomers

Instead of 5-(benzyloxy)-1,1,1-trichloropent-3-yn-2-one (see Example No.2), 1,1,1-trichloro-5-(tetrahydro-2H-pyran-2-yloxy)pent-3-yn-2-one wasused. The preparation was analogous to that described in Example No. 2.

Characterization of the Resulting Diastereomer Mixture:

¹H NMR (CDCl₃): 1.46-1.58 (4H); 1.66-1.73 (1H, m); 1.75-1.8 (1H, m);3.48 (1H, m); 3.81 (1H, m); 3.33 (1H, d); 3.81 (1H, d); 7.21 (1H, dd);7.23 (1H, dd); 7.94 (1H, dd); 8.22 (1H, dd); 9.48 (1H, bs) ppm.

Example 42-{3-[(Benzyloxy)methyl]-5-(trichloromethyl)-1H-pyrazol-1-yl}-3-chloropyridine

4.35 g of3-[(benzyloxy)methyl]-1-(3-chloropyridin-2-yl)-5-(trichloromethyl)-4,5-dihydro-1H-pyrazol-5-olwere dissolved in 30 ml of methyl isobutyl ether. Then 3 g oftrifluoroacetic anhydride were added (exothermic reaction). The mixturewas stirred at 25° C. for a further 2 h, in the course of which theprecipitate was formed. The precipitate was filtered off and washed. Theyield was 95%.

Characterization:

¹H NMR (CDCl₃): 4.60 (2H, s); 4.62 (m, 2H), 6.95 (1H, s); 7.2-7.4 (5H,m); 7.42 (1H, m); 7.95 [(1H, d, 2 Hz)]; 8.5 [(1H, d, 2 Hz)] ppm.

Melting point (m.p.): 211-213° C.

Example 53-[(Benzyloxymethyl]-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylicacid

4.4 g of2-{3-[(benzyloxy)methyl]-5-(trichloromethyl)-1H-pyrazol-1-yl}-3-chloropyridineand 30 ml of 20% H₂SO₄ were heated at 100° C. for 24 h.

The precipitate was filtered off and washed with water. The yield was92%.

Characterization:

¹H NMR (CDCl₃): 4.61 (2H, s); 4.63 (m, 2H), 6.97 (1H, s); 7.2-7.4 (5H,m); 7.42 (1H, m); 7.96 [(1H, d, 2 Hz)]; 8.5 [(1H, d, 2 Hz)] ppm.

Example 61-(3-Chloropyridin-2-yl)-3-(hydroxymethyl)-1H-pyrazole-5-carboxylic acidhydrochloride

3.43 g of3-[(benzyloxy)methyl]-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylicacid and 20 ml of HCl (37.5%) were heated at 100° C. for 2 h and thenthe reaction mixture was completely concentrated under reduced pressureat 10 mbar. This gave1-(3-chloropyridin-2-yl)-3-(hydroxymethyl)-1H-pyrazole-5-carboxylic acidas the hydrochloride. Neutralization with NaHCO₃ afforded the free acidas a white solid. The yield was 94%.

Example 7 Methyl3-(chloromethyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate

1-(3-Chloropyridin-2-yl)-3-(hydroxymethyl)-1H-pyrazole-5-carboxylic acidhydrochloride (0.1 mol) was initially charged in 50 ml of toluene, SOCl₂was added in portions at 60° C. The mixture was heated at 70° C. for 3h, in the course of which the precipitate went completely into thesolution. Methanol (30 ml) was slowly added dropwise to the mixture andthe solution was stirred at room temperature for one hour. Subsequently,the solution was concentrated under reduced pressure. This afforded 95%of the product with a purity of 96% (area percent).

Characterization

¹H NMR (CDCl₃): 3.7 (3H, s); 4.7 (2H, s); 7.1 (1H, s); 7.5 (1H, m); 8.05[(1H, m)]; 8.5 [(1H, m)] ppm.

1. Process for preparing pyridyl-substituted pyrazole derivatives of thegeneral formula (I)

in which R¹ is alkoxy, hydroxyl, aryloxy, alkylaryloxy, alkyl,cycloalkyl, halogen, R² is hydroxyl, alkoxy, arylalkoxy, alkylthio,chlorine, bromine, fluorine, iodine, O—(C═O)alkyl, O—(C═O)O-alkyl,OSO₂alkyl, OSO₂Ph, OSO₂-haloalkyl, OSO₂-aryl, characterized in that (A)acetyleneketones of the formula (II)

in which R⁴ is a protecting group selected from (C₁-C₆)-alkyl, aryl,benzyl, tetrahydropyran, (C═O)-alkyl, (C═O)—Oalkyl, Si(alkyl)₃, and X ishalogen are reacted with hydrazinopyridines of the formula (III)

in which R³ is halogen, CN, NO₂, alkyl, cycloalkyl, haloalkyl,halocycloalkyl, alkoxy, haloalkoxy, alkylamino, dialkylamino,cycloalkylamino, to give 1-pyridyl-substituted dihydro-1H-pyrazoles ofthe formula (IV)

in which X, R³, R⁴ are each as defined above, (B) the latter areoptionally converted further, without preceding isolation, withelimination of water, to 1-pyridyl-substituted trihalomethylpyrazoles ofthe formula (V)

in which X, R³, R⁴ are each as defined above, (C) these compounds of thegeneral formula (V) are converted with addition of H₂SO₄, for example,to pyrazolecarboxylic acids of the formula (VI)

in which R³, R⁴ are each as defined above, (D) the latter are converted,after detaching the protecting group R⁴, to hydroxymethylpyrazole acidsof the formula (VII)

in which R³ is as defined above, and (E) the latter are converted tocompounds of the formula (I).
 2. Process for preparing compounds of theformula (I) according to claim 1, characterized in that R¹ is(C₁-C₆)-alkoxy, halogen, R² is (C₁-C₆)-alkoxy, aryl(C₁-C₆)-alkoxy,fluorine, chlorine, bromine, iodine, R³ is halogen, CN, NO₂,(C₁-C₆)-alkyl, halo(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, halo(C₁-C₆)alkoxy. 3.Process for preparing compounds of the formula (I), characterized inthat the preparation of the compound of the formula (V) comprises steps(A) and (B) according to claim
 1. 4. Process for preparing compounds ofthe formula (I) according to claim 3, characterized in that thecompounds of the formula (V)

in which X is halogen, R⁴ is a protecting group selected from(C₁-C₆)-alkyl, aryl, benzyl, tetrahydropyran, (C═O)-alkyl, (C═O)—Oalkyl,Si(alkyl)₃, R³ is halogen, CN, NO₂, alkyl, cycloalkyl, haloalkyl,halocycloalkyl, alkoxy, haloalkoxy, alkylamino, dialkylamino,cycloalkylamino, are converted by detaching the protecting group tocompounds of the formula (VIII)

in which X, R³ are each as defined above, the latter are converted byhydrolysis to compounds of the general formula (VII)

in which R³ is as defined above, and the latter are converted withaddition of a halogenating agent and subsequent alcohol addition tocompounds of the formula (I).
 5. Process for preparing compounds of theformula (I) according to claim 3, characterized in that the compounds ofthe formula (V) in which X is halogen, R⁴ is a protecting group selectedfrom (C₁-C₆)-alkyl, aryl, benzyl, tetrahydropyran, (C═O)-alkyl,(C—O)—Oalkyl, Si(alkyl)₃, R³ is halogen, CN, NO₂, alkyl, cycloalkyl,haloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkylamino, dialkylamino,cycloalkylamino, are converted with addition of alcohol directly to theinventive compounds of the formula (I).
 6. Compounds of the formula (I)according to claim 1, characterized in that R¹ is halogen, R² isfluorine, chlorine, bromine, iodine, R³ is halogen, CN, NO₂, alkyl,cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkylamino,dialkylamino, cycloalkylamino.
 7. Compounds of the formula (IV)according to claim 1, characterized in that X is halogen, R³ ischlorine, R⁴ is benzyl.
 8. Compounds of the formula (V) according to anyof claims 1 to 5, characterized in that X is halogen, R³ is chlorine, R⁴is benzyl.
 9. Compounds of the formula (V) according to claim 8,characterized in that X is chlorine.
 10. Compounds of the formula (VII)according to claim 1 or 4, characterized in that R³ is halogen, CN, NO₂,alkyl, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, haloalkoxy,alkylamino, dialkylamino, cycloalkylamino.